The proposal is a 5-year program to enable an independent career in academic medical research, focusing on fungal pathogenesis and host response. This will occur in a collaborative environment at the Whitehead Institute and Harvard Medical School. Invasive fungal infections remain a threat to hospitalized patients. While C. albicans is the most significant pathogenic yeast, non-albicans species account for close to 50% of these infections. Initial interactions between fungi and innate immune cells present the first line of defense against these pathogens. Fungal surface adhesive proteins (adhesins) likely mediate these events. Despite the ubiquity of adhesins, and their binding to epithelial cells, little has been reported about interactions with the immune system. In addition, available data on host receptors cannot explain many aspects of fungal-host relationships. Macrophages are key components of the innate immunity, mediating effector cell and adaptive immunity. A novel C. glabrata adhesin, Epa1p, was recently shown to bind epithelial cells. My preliminary data indicates this is a novel, powerful, mediator of adherence to macrophages. Results indicate downstream effects include modulation of immune responses. I aim to understand how Epa1p mediates interactions with the innate immune system, leading to infection and immunomodulation. After identifying key binding behaviors, we will examine how this interaction affects macrophage mRNA and cytokine expression. To model human pathogenesis, I will utilize established murine models of infection. In addition, I will examine efficacy of both active (with Epa1p) and passive (with anti-Epa1p antibody) immunization in these models. Given the widespread distribution of these proteins in pathogenic fungi, the data will provide a paradigm for the behavior of fungal adhesins, applicable to a host of pathogens. This work will better define how fungal binding leads to immune modulation. This in turn will be expected to produce a) targets for novel antifungal agents, b) methods for active and passive immunization, c) potential diagnostic markers, and d) new avenues for immunomodulatory drugs.